Kampo medicine for improving cognitive function in alzheimer-type dementia or mild cognitive impairment and treating at least one disease from the group consisting of overactive bladder, constipation, and chronic kidney diseases complicated by them with one drug

ABSTRACT

Provided is a kampo medicine for treating multimorbidity of Alzheimer-type dementia or mild cognitive impairment and at least one disease from the group consisting of overactive bladder, constipation, and chronic kidney disease with one drug. A kampo medicine for treating multimorbidity with one drug, comprising a drug combination of orengedokuto and ryokeijutsukanto as an active ingredient, wherein the kampo medicine improves a cognitive function in Alzheimer-type dementia or mild cognitive impairment and relieves and treats at least one disease from overactive bladder, constipation, and chronic kidney disease complicated by Alzheimer-type dementia or mild cognitive impairment at a high rate with one drug.

RELATED APPLICATIONS

The present application claims priority from Japanese patent applicationJP 2018-69196 filed on Mar. 30, 2018, the content of which is herebyincorporated by reference into this application.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a composition for treatingmultimorbidity with one drug, comprising a drug combination of kampomedicines, wherein the composition improves a cognitive function inAlzheimer-type dementia or mild cognitive impairment and treats at leastone disease from the group consisting of overactive bladder,constipation, and chronic kidney disease complicated by them with onedrug.

2. Description of the Related Art

As in the publication by Boyd et al. in JAMA in 2005 (Boyd C. M. et al.,JAMA, 294(6): 716-724, 2005), multimorbidity is defined as thecoexistence of 2 or more chronic diseases simultaneously. It has beenreported that 67% of 30,923,846 people who were continuously enrolled inMedicare during 2008 in U.S.A. were affected by multimorbidity and theprevalence of multiple chronic diseases increases with age to 81.5% at85 or more years old (Marcel E. Salive et al.,: Multimorbidity in OlderAdults. Epidemiology Reviews, Vol 35, Issue 1, 1 Jan. 2013, 75-83,https://doi.org/10.1093/epirev/mxs009). It has been reported that in anexamination of the frequency of multimorbidity focused on only 40chronic diseases in the U.K., 42.2% were affected by only one diseaseand 23.2% were affected by multimorbidity having 2 or more diseases(Anthiens S et al., BMC Fam Pract, 11:65, 2010). As a result, theexistence of multiple chronic diseases naturally increases the number ofadministered medicines. The study of 700 elderly persons by Fushiki etal. at Jichi Medical University reported that men and women at anaverage age of 79.5 take an average of 6.36 drugs, and polypharmacy with5 or more drugs was 63% (Fushiki Y et al., General Medicine, 15(2):110-116, 2014). In addition, a cohort study by Green et al. reportedthat one more prescriber for a multimorbidity patient increases drugadverse events by 29% (Green J L et al., Am J Geriatr. Pharmacother,5(1): 31-39, 2007). In other words, multimorbidity is the biggest causeof polypharmacy and polypharmacy is the biggest cause of the increase ofside effects due to drugs and the increase in drug cost and medicalexpense, and has therefore been a global problem. Currently, guidelinesfor single chronic diseases exist for each of a large number of chronicdiseases, but since the guidelines for single chronic diseases are notindicated for multimorbidity, the existing guidelines cannot now be usedfor multimorbidity. Only the guidelines having a description ofrecommendation for cases with multiple complications are those fordiabetes and angina. It is the present conditions that no accurateguidelines for the multimorbidity exist. Studies on how to actually dealwith multimorbidity is necessary (Smith S M et al., BMJ, 345: e5205,2012) and the website of The Johns Hopkins School of Medicine emphasizesthat studies for preventing multimorbidity should be promoted (Boyd C etal., Center for Health Care Strategies. Inc., 2010).

Also in Japan, it has been reported that, according to the statistics ofthe Japan Society of Ningen Dock (complete medical check), the supernormals, who don't have abnormality in any of the basic items, were29.8% in 1984, when the aggregation of the results started, butdecreased every year to 6.6% in 2014, which was the lowest ever (JapanSociety of Ningen Dock: Report on National Aggregate Results of NingenDock in 2014, 2014). It is considered that multimorbidity is certainlyincreasing and the development of the measures is urgent business.

Dementia is an intellectual disability caused by acquired causes androughly classified into Alzheimer-type dementia, mixed dementia ofAlzheimer-type dementia and cerebrovascular dementia, cerebrovasculardementia, dementia with Lewy bodies, normal pressure hydrocephalus, andfrontotemporal syndromes. The main diseases of senile dementia-relateddiseases are Alzheimer-type dementia and cerebrovascular dementia, whichaccount for 75% to 80% and Alzheimer-type dementia is considered to bepredominantly at a higher rate. The prevalence of dementia at 30 yearsor older is reported to be 4 to 6% in developed regions in Europe, theAmericas and the West Pacific, but increases to 20% to 33% for elderlypersons at 85 years or older. Patients with dementia will continueincreasing at a ratio of 4,600,000 people/year from now and areestimated to increase to 42,300,000 in 2020 and to 81,100,000 in 2040,and it is considered that dementia will increase rapidly all over theworld from now on (Ferri C P et al., Lancet, 2005; 366: 2112-2117). Inother words, while Alzheimer-type dementia has been increasing, it isthe biggest problem in that no therapy for dementia, includingAlzheimer-type dementia, except normal pressure hydrocephalus andcerebrovascular dementia, has been established in the present, becausethe cause has not been determined.

Mild cognitive impairment (MCI) is a concept proposed in 1999 byPetersen et al. (Petersen R C, et al., Arch Neurol, 56: 303-308, 1999)and diagnostic criteria (Petersen R C, et al., Arch Neurol, 62:1160-1163, 2005) newly proposed by Petersen et al. in 2003 are used forthe diagnosis of mild cognitive impairment (MCI) now. In other words,mild cognitive impairment is defined to be a condition in which thereare claims of cognitive decline from the subject oneself or his family,cognitive functions are not normal, but without meeting the diagnosticcriteria for dementia, and there is a minimum disorder in complicateddaily life movements, but basic everyday life can be spent normally. Inother words, no behavior and psychological symptoms of dementia (BPSD)is observed in mild cognitive impairment (MCI). It has been reportedthat as a result of a follow-up study by Petersen et al. at Mayo Clinicof subjects with MCI by their criteria for 15 years or more, thesubjects progressed to dementia or probable AD at an average ratio of12% per year and about 80% developed dementia in 6 years (Petersen R C,et al., Mild cognitive impairment, New York: Oxford UP; 2003, P. 15-39).From this result, it is considered that improving mild cognitiveimpairment (MCI) would naturally reduce the patients who developAlzheimer-type dementia. However, the results of clinical trials withdonepezil hydrochloride for MCI were reported in 2005, and it wasreported that progress of dementia can significantly he suppressed byintake of donepezil hydrochloride for one year, but there is nopreventive effect on the disease progression afterward (Petersen R C etal., N Engl J Med, 2005: 352: 2379-88), indicating that administrationof donepezil hydrochloride eventually results in the same course ofcognitive decline as that without treatment after one year. In otherwords, like there is no effective drug that improves cognitive functionsin Alzheimer-type dementia developed, no effective drug that amelioratescognitive decline has been successfully developed also for mildcognitive impairment (MCI) (Doody R S et al., Neurology, 72: 1555-1561,2009).

Multimorbidity is easy to occur in Alzheimer-type dementia or mildcognitive impairment and complications with constipation and/oroveractive bladder are developed at a high rate as an autonomic nervoussystem disorder. In other words, the frequency of normal chronicconstipation is reported to be 0.7 to 79% (median 16%) according tosystematic review (Mugie S M et al., Best Pract Res Clin Gastroenterol,25(1): 3-18, 2011). Since most of patients with Alzheimer-type dementiaor mild cognitive impairment are old in age, constipation is afrequently observed complication. It has been reported that among 7,758elderly persons in nursing facilities or at home, 73.7% have cognitiveimpairment and 1,967 persons (25.4%) have constipation (Takaue Sachikoet al.: Fact-finding of excretion care for elderly person in MiePrefecture. Mie nursing journal, 9:111-116, 2007).

As to overactive bladder, Irwin et al. have reported that 11.8% ofgeneral population at 18 years or older has overactive bladder and thefrequency increases with age (Debra E. Irwin et at, European Urology,50: 1306-1315, 2006) and it has been reported that incontinence is verycommon in elderly persons and it is observed in 5 to 10% of at-homeelderly persons and about 50% of elderly persons in institution (KikuoOkamura, et al., Guidelines on Urinary Incontinence in the Elderly(http://www.negg.go.jp/hospital/iryokankei/documents/guidelines.pdf), P.6-15). Furthermore, it has been reported that 44% of patients withAlzheimer-type dementia have nocturia, which is one of the diagnosticcriteria for overactive bladder (Takahashi O et al., J Am Geriatr Soc,60: 2370-2371, 2012).

Furthermore, the number of patients with chronic kidney disease (CKD) inU.S.A. is about 13% of the adult population according to National Healthand Nutrition Examination Survey (NHANES). In Japan, the number ofpatients with chronic kidney disease (CKD) is reported to be 13% of theadult population and 13 million persons (Imai, E., et al., Clin. Exp.Nephrol., 11(2), 156-163, 2007). Cardiovascular Health Cognition Studyhas indicated that moderate renal dysfunction increases development ofdementia by 37% (Seliger S L, et at, J Am Soc Nephrol, 15: 1904-1911,2004). Furthermore, most of Alzheimer-type dementia patients are easy tohave decreased renal functions due to the age since they are old andeasy to have complications with chronic kidney disease (CKD).

In other words, Alzheimer-type dementia and mild cognitive impairmentare complicated by constipation and overactive bladder at high rates dueto autonomic nervous system disorders, and complications with chronickidney disease are found frequently and multimorbidity is observedfrequently. However, no effective guidelines for any combination ofAlzheimer-type dementia or mild cognitive impairment and complicationdiseases thereof and no therapeutic agents specific for thismultimorbidity exist.

Only therapeutic drugs for Alzheimer-type dementia are 3acetylcholinesterase inhibitors (donepezil hydrochloride, galanthamine,rivastigmine) and 1 low affinity N-methyl-D-asparagine receptorantagonist (memantine). These are medicines for ameliorating symptomsand the effect of any drug on cognitive function is transient. Thesecannot suppress progression of Alzheimer-type dementia and no radicaltherapeutic effect is expected. The clinical trial with an activeamyloid vaccine produced based on the hypothesis that the cause ofAlzheimer-type dementia is β amyloid, as a radical therapy, was canceledbecause of meningoencephalitis. In the subsequent course, it wasindicated that the accumulation of amyloid β in the brain was reduced,but the progression of dementia could not be suppressed (Lannfelt L etal., J Intern Med, 275: 284-295, 2014).

The therapeutic agents for Alzheimer-type dementia currently used ingeneral themselves have the side effects of constipation, pollakiuria,and urinary incontinence. Therapeutic agents for overactive bladderother than mirabegron have the side effect of constipation, andsolifenacin and mirabegron have the side effect of increasingcreatinine. As a result, treatment of Alzheimer-type dementia and mildcognitive impairment, which are complicated by constipation, overactivebladder, and/or chronic kidney disease at a high rate is very difficultand easy to result in polypharmacy.

Even now, to patients with Alzheimer-type dementia or mild cognitiveimpairment complicated by constipation, overactive bladder, and/orchronic kidney disease, drugs for respective diseases are administeredwithout any hesitation, resulting in polypharmacy. Therefore, the sideeffects become complicated and the frequency of side effects will beincreased. It is also a problem in that the interaction of drugs hasbeen studied only for two drugs and the interactions and side effects inpolypharmacy are difficult to expect.

As to kampo medicine therapies, Jingui Yaolue written in the early thirdcentury A.D. describes an instruction to administer boijioto fordementia. However, the results of studies have indicated thatadministration of kampo medicines for Alzheimer-type dementiaameliorates symptoms such as behavior and psychological symptoms ofdementia (BPSD), but there is no kampo medicine having a radicaltherapeutic effect that improves cognitive functions in the long term.Yokukansan, which is used the most often for Alzheimer-type dementia, isadministered for BPSD (Hideki Okamoto et al., Neuropsychiatric Diseaseand Treatment, 10, 1727-1742, 2014). The 2017 Therapeutic Guidelines forDementia by the Japanese Society of Neurology states that yokukansan isused for the suppression of BPSD in dementia with Lewy bodies (theJapanese Society of Neurology: The 2017 Therapeutic Guidelines forDementia., 254-256, 2017). Moreover, when the BPSD suppressing effect isnot obtained only with yokukansan, additional administration oforengedokuto, which is used for cerebrovascular disorder-relateddementia, resulted in the suppression of BPSD, but the improvement ofcognitive functions has not been described (Hideki Okamoto et al.,Neuropsychiatric Disease and Treatment, 9, 151-155, 2013). In otherwords, this not only fails to improve cognitive functions, but also istotally far away from and unrelated to a drug for the purpose ofrelieving constipation, overactive bladder, and chronic kidney disease,which are other diseases that are complicated by Alzheimer-type dementiaor mild cognitive impairment at high rates, with one drug and it issomething totally different. There is a report that the administrationof Hangebyakujutsutemmato improved cognitive functions (Yoshiharu NAKAE,et al., Kampo Med, 64, 104-107, 2013), but the observation period was 4weeks, and it cannot relieve constipation, overactive bladder, andchronic kidney disease, which are diseases that are complicated byAlzheimer-type dementia frequently, more than considered to be onlytemporary like donepezil hydrochloride. In other words, despite ofstudies for a very long period of 1700 years to develop cognitivefunction-improving medicines for Alzheimer-type dementia and mildcognitive impairment, the development of a kampo medicine that improvescognitive functions has been extremely difficult and no one in the arthas been able to develop a drug that ameliorates multimorbidity ofconstipation, overactive bladder, and chronic kidney disease, which arecomplicated by Alzheimer-type dementia and mild cognitive impairmentfrequently, with one drug.

Moreover, although various kampo medicines including Bofutsushosan havebeen used for constipation (Norio Iizuka et al., Frontiers inPharmacology. 6. Article 73.2015. www.frontiersin.org) to get results,kampo medicines mainly including Goshajinkigan have been used foroveractive bladder (Tomonori Miyagawa et al., Int. J Urol., 22, 254-263,2015), and kampo therapeutics such as Boiogito have been used forchronic kidney disease (CKD) (Hong Wei Zhang, et al., Cochrane Databaseof Systematic Reviews, 10, 1-21, 2014), there are few medicines foroveractive bladder and chronic kidney disease that have been clinicallyrecognized and yielded long term results.

In recent years, Alzheimer-type dementia and mild cognitive impairmentas well as diseases complicated by them have markedly increased.However, in multimorbidity of Alzheimer-type dementia or mild cognitiveimpairment, it is very difficult to relieve these diseases themselvesand each individual disease of constipation, overactive bladder, andchronic kidney disease complicated by them. Moreover, since thismultimorbidity is a collection of diseases in different fields that area digestive organ disease, an urinary organ disease, and a renal diseasecomplicated by a neurological disease, there is not even an idea ofrelieving these multiple diseases with one drug at the same time, andtherefore there is no researcher or person skilled in the art of kampomedicines who studies drugs that can treat diseases complicated in thesemultimorbidity at the same time with one drug. Naturally, there is noreport of research findings on these therapeutic agents formultimorbidity and consequently, there is no such drug.

SUMMARY OF THE INVENTION

The present invention provides a composition for treating multimorbiditywith one drug, comprising a drug combination of orengedokuto andryokeijutsukanto as an active ingredient, wherein the compositionimproves a cognitive function in Alzheimer-type dementia or mildcognitive impairment and treats at least one disease from the groupconsisting of overactive bladder, constipation, and chronic kidneydisease complicated by them with one drug.

It has been considered to be impossible to cure complicated diseases indifferent fields of neurological disease, digestive organ disease,urinary organ disease, and renal disease with one drug and developmentof such a drug has not been conducted. The present inventors havestudied diligently and developed a drug that can cure multiple diseasesof any combination of Alzheimer-type dementia or mild cognitiveimpairment with constipation, overactive bladder, and/or chronic kidneydisease at the same time with one drug, that is to say, a mixed kampomedicine of orengedokuto and ryokeijutsukanto that can treatmultimorbidity of Alzheimer-type dementia or mild cognitive impairment,thereby completing the present invention.

Accordingly the present invention is as follows:

[1] A kampo medicine for treating multimorbidity with one drug,comprising a drug combination of orengedokuto (Formula antidotecoptidis) and (Formula glycyrrhizae atractylodis cinnamomi hoelen)ryokeijutsukanto as an active ingredient, wherein the kampo medicineimproves a cognitive function in Alzheimer-type dementia and relievesand treats at least one disease from overactive bladder, constipation,and chronic kidney disease complicated by Alzheimer-type dementia at ahigh rate with one drug.

[2] A kampo medicine for treating multimorbidity with one drug,comprising a drug combination of orengedokuto (Formula antidotecoptidis) and (formula glycyrrhizae atractylodis cinnamomi hoelen)ryokeijutsukanto as an active ingredient, wherein the kampo medicineimproves a cognitive function in mild cognitive impairment and relievesand treats at least one disease from overactive bladder, constipation,and chronic kidney disease complicated by mild cognitive impairment at ahigh rate with one drug.

The composition comprising a drug combination of orengedokuto andryokeijutsukanto as an active ingredient according to the presentinvention improves cognitive functions in Alzheimer-type dementia ormild cognitive impairment and relieves and treats at least one diseasefrom the group consisting of overactive bladder, constipation, andchronic kidney disease complicated by them with one drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates comparison of HDS-R (n=9) at the starting time andthe ending time of observation of the control group;

FIG. 2 illustrates comparison of HDS-R (n=40) before and afteradministration of a mixed kampo medicine of orengedokuto andryokeijutsukanto;

FIG. 3 illustrates comparison of HDS-R at the starting time of theobservation of the control group and before the administration of themixed kampo medicine of orengedokuto and ryokeijutsukanto; and

FIG. 4 illustrates comparison of HDS-R at the ending time of theobservation of the control group and after the administration of themixed kampo medicine of orengedokuto and ryokeijutsukanto.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be described in detail below.

The composition according to the present invention is a kampo medicinewhich is a drug combination of orengedokuto (Formula antidote coptidis)and ryokeijutsukanto (Formula glycyrrhizae atractylodis cinnamomihoelen), comprising orengedokuto and ryokeijutsukanto as an activeingredient.

Orengedokuto is a kampo medicine formulated from the crude drugs CoptisRhizome (Coptidis Rhizoma), Scutellaria Root (Scutellariae Radix),Phellodendron Bark (Phellodendri Cortex), and Gardenia Fruit (GardeniaeFructus). The mixed weights of the dried crude drugs in a daily dose foran adult are, for example, 1.5 g to 2.0 g for Coptis Rhizome, 3.0 g forScutellaria Root, 1.5 g to 3.0 g for Phellodendron Bark, and 2.0 g to3.0 g for Gardenia Fruit.

Coptis Rhizome, Scutellaria Root, Phellodendron Bark and Gardenia Fruitwill be described below, but they may indicate things other than thoseset forth below. Coptis Rhizome refers to a dried rhizome of Coptisjaponica Makino in the family Ranunculaceae or another plant in the samegenus, from which most of the roots have been removed. Scutellaria Rootrefers to a dried root of Scutellaria baicalensis Georgi in the familyLabiatae, from which the periderm has been removed. Phellodendron Barkrefers to a dried bark (phelloderm) of Phellodendron amurense RUPR. inthe family Rutaceae or another plant in the same genus, from which theperiderm has been removed. Examples of the another plant in the samegenus include Phellodendron chinense Schneider. Gardenia Fruit refers toa dried fruit of Gardenia jasminoides ellis in the family Rubiaceae oranother plant in the same genus.

Orengedokuto can be prepared by obtaining the extract preparations ofthe 4 crude drugs described above and mixing them according to the mixedweights described above. Alternatively, it can be prepared by puttingthe 4 dried crude drugs of the mixed weights described above in 600 mlof hot water, and boiling it down (concentrating) to 300 ml for onehour, the yielded 300 ml being a daily amount. The two kampo medicines,100 ml each a time, may be mixed to 200 ml a time to be administeredthree times a day before every meal. The two kampo medicines, 150 mleach a time, may be mixed to 300 ml a time to be administered twice aday before morning and evening meals.

Commercial medicines are also available. The commercial medicinesinclude OHSUGI orengedokuto Extract T Tablets (Ohsugi PharmaceuticalCo., Ltd), Kracie Orengedokuto Extract Tablets (Kracie Pharmaceutical,Ltd.), KOTARO Orengedokuto Extract Fine granules (Kotaro pharmaceuticalCo., Ltd.), SAKAMOTO orengedokuto Extract granule-S (Sakamoto KanpohPharmaceutical Co., Ltd.), TSUMURA Orengedokuto Extract granules forEthical Use (TSUMURA & CO.), and JPS Orengedokuto Extract granules forEthical Use (JPS Pharmaceutical Co., Ltd.).

Ryokeijutsukanto is a crude drug formulated from Poria Sclerotium(Hoelen), Atractylodes Lancea Rhizome (Atractylodis Lanceae Rhizoma) orAtractylodes Rhizome (Atractylodis Rhizoma), Cinnamon Bark (CinnamomiCortex), and Glycyrrhiza (Glycyrrhizae Radix). The mixed weight ratio ofthe dried crude drugs in a daily dose for an adult is, for example, 4 gto 6 g for Poria Sclerotium, 2 g to 3 g for Atractylodes Lancea Rhizomeor Atractylodes Rhizome, 3 g to 4 g for Cinnamon Bark, and 1 g to 2 gfor Glycyrrhiza.

Poria Sclerotium and Cinnamon Bark will be described below, but they mayindicate things other than those set forth below. Atractylodes LanceaRhizome or Atractylodes Rhizome and Glycyrrhiza are as described above.

Poria Sclerotium refers to a dried sclerotium of Poria cocos Wolf in thefamily Polyporaceae, as it is or from which most of the shell isremoved. Cinnamon Bark refers to a dried bark of Cinnamomum cassia Blumein the family Lauraceae or another plant in the same genus.

The extracts of the crude drugs contained in orengedokuto orryokeijutsukanto may be, for example, extracted with water or hot water,ethanol, acetic acid from the crude drugs, dried by spray-drying orfreeze-drying, and used as powder. The powders are mixed to produceorengedokuto or ryokeijutsukanto and these are mixed to produce the drugcombination.

The drug combination of orengedokuto and ryokeijutsukanto may beprepared by mixing 2.5 to 10 g, preferably 5 to 10 g, more preferably 7to 8 g, particularly preferably 7.5 g of the dried extract powder oforengedokuto and 2.5 to 10 g, preferably 5 to 10 g, more preferably 7 to8 g, particularly preferably 7.5 g of the dried extract powder ofryokeijutsukanto for a daily adult dose. In this case, the two kampomedicines, 100 ml each a time, may be mixed to 200 ml a time to beadministered three times a day before every meal. The two kampomedicines, 150 ml each a time, may be mixed to 300 ml a time to beadministered twice a day before morning and evening meals. Whencommercial kampo medicine extracts are used, 1/3 of indicated dailydoses of a commercial orengedokuto extract and a commercialryokeijutsukanto may be mixed and administered three times a day beforemeals. Halves of indicated daily doses of a commercial orengedokutoextract and a commercial ryokeijutsukanto may be mixed and administeredtwice a day before morning and evening meals. The composition accordingto the present invention can be obtained by adding the mixture to anappropriate excipient, a pharmaceutic aid or the like used for usualformulation and formulate an oral formulation such as powder, a granule,a tablet, a capsule, a solution, a syrup, or the like according to aconventional method of the formulation production. Other than them, anappropriate binder, a disintegrator, a surfactant, a corrigent, and/or aflavor may be combined. Examples of the excipient include starch,dextrin, lactose, saccharose, mannite, microcrystalline cellulose, andanhydrous silicic acid.

The composition according to the present invention usually containsaround 0.1 to 100% by weight of orengedokuto and ryokeijutsukantorelative to the total composition, which may vary depending on itsdosage form. The dose of the composition according to the presentinvention to a patient may be administered once a day or divided intoseveral divided doses and administered several times a day for severaldays to several tens of months or several years to ten and severalyears, taking the age of the patient into consideration.

The drug combination of orengedokuto and ryokeijutsukanto according tothe present invention is a kampo medicine that treats at least onedisease from the group consisting of Alzheimer-type dementia or mildcognitive impairment (MCI) and associating overactive bladder,constipation, and chronic kidney disease with one drug. Patients withAlzheimer-type dementia or patients with mild cognitive impairment oftenhave complications with one, two, or three diseases selected from thegroup consisting of overactive bladder, constipation, and chronic kidneydisease at high rates. For example, in a study with 18 patients withAlzheimer-type dementia and 22 patients with mild cognitive impairmentconducted by the present inventors, 92.5% of the patients withAlzheimer-type dementia or with mild cognitive impairment hadcomplications with any of overactive bladder, constipation, and chronickidney disease, 82.5% had complications with overactive bladder, 72.5%had complications with constipation, and 50% had complications withchronic kidney disease. Such conditions with multiple diseases at thesame time are referred to as multimorbidity. Moreover, patients havingcomplications with all of overactive bladder, constipation, and chronickidney disease were 32.5%, patients having complications with 2 diseasesfrom overactive bladder, constipation, and chronic kidney disease are47.5%, and patients having no complication with any of the diseases were7.5%. The drug combination of orengedokuto and ryokeijutsukantoaccording to the present invention may improve the cognitive function ofpatients with Alzheimer-type dementia or mild cognitive impairment andrelieve and treat one, two or three diseases from the group consistingof overactive bladder, constipation, and chronic kidney diseasecomplicated by Alzheimer-type dementia or mild cognitive impairment.Accordingly, the drug combination of orengedokuto and ryokeijutsukantoaccording to the present invention is a kampo medicine for treatingmultimorbidity of Alzheimer-type dementia or mild cognitive impairmentand at least one disease from the group consisting of overactivebladder, constipation, and chronic kidney disease with one drug.

Alzheimer-type dementia refers to dementia manifested in patients withAlzheimer's disease, which is a neurodegenerative disease that causesbrain atrophy.

Mild cognitive impairment corresponds to the stage before dementia,considered to be an intermediate stage between a healthy subject anddementia, and refers to a condition in which the cognitive function islowered than that expected in the normal aging process but not as low asto be called dementia. Definitions of mild cognitive impairment includethe following three: 1. the person oneself or his family claimscognitive decline memory, judgment, reasoning, execution); 2. thecognitive function is not normal, but without meeting diagnosticcriteria for dementia; and 3. there is a minimum disorder in complicateddaily life movements, but everyday life can be spent normally.

Alzheimer-type dementia and mild cognitive impairment can be diagnosedby Hasegawa Dementia Scale (HDS-R) and Mini Mental State Examination(MMSE). Hasegawa Dementia. Scale (HDS-R) is a test for investigating atendency of dementia from the result of test of total 30 points withtotal 9 items. MMSE is a test of total 30 points with 13 questions of 9items that covers orientation, memory, calculation, language ability,graphic ability, and the like.

If the result of an HDS-R test is 20 points or more, then the cognitivefunction is normal and it can be determined that Alzheimer-type dementiaor mild cognitive impairment has been ameliorated.

Overactive bladder refers to dysuria with a feeling of urinary urgencyby bladder's involuntary contractions. Overactive bladder is diagnosed,for example, when there is a feeling of urinary urgency and thefrequency of urination at night is 3 times or more. It can be determinedthat overactive bladder is relieved and successfully treated when thefrequency of urination at night is once or less.

Constipation refers to infrequent bowel movements caused by variouscauses such as lifestyles, diseases, side effects of drugs, and thelike. It can be determined whether a subject has constipation or notbased on Rome III diagnostic criteria (Longstreth G F, et al.,Gastroenterology 130: 1480-1491, 2006). It can be determined whetherconstipation is relieved and successfully treated based on the criteria.

Chronic kidney disease (CKD) refers to a condition in which a kidneydisorder continues chronically. Chronic kidney disease is diagnosed whenthere is persistence of any or both of a renal disorder (occurrence ofproteinuria or bloody urine, observation of injury by diagnosticimaging, or the like) and a lowered renal function (an eGFR (estimatedglemerular filtration rate) of less than 60 ml/min./1.73 m²) for 3months or more. For example, when the eGFR (estimated glemerularfiltration rate) is 60 ml/min./1.73 m² or more, it can be determinedthat chronic kidney disease is relieved and successfully treated.

As to the dose of the drug combination of orengedokuto andryokeijutsukanto according to the present invention, for example, whencommercial medical kampo medicine extract formulations are used at adaily dose of 7.5 g for an adult, a mixed drug combination of 2.5 g eachof the kampo medicines may be orally administered three times a daybefore meal. The medicines are administered until symptoms of thepatient are relieved, which varies depending on the reaction of thepatient.

Furthermore, the composition according to the present invention may beadmixed into food or a beverage and used as a food or drink compositionor a feeding-stuff composition. In such a use, orengedokuto andryokeijutsukanto may be mixed into a single intake amount of the food ordrink or feeding-stuff, for example, at a ratio of 100 mg/kg, when thedaily dose of commercial medical kampo medicine extracts for a person is7.5 g. The composition according to the present invention may be used asa food or drink composition or a feeding-stuff composition in a form ofpowder, granules, liquid, paste, or the like. Beverages and foodsinclude foods with function claims, health beverages and foods,beverages and foods for specified health uses, functional nutritionalbeverages and foods, and beverage or food supplements. As used herein,foods for specified health uses refer to foods that are taken for aspecific health purpose in diets and have an indication that the healthpurpose may be achieved by the intake. Moreover, foods with functionclaims refer to foods displaying functionality on their product packagesbased on a chemical basis on the responsibility of the organization ofthe products. The composition according to the present invention mayhave a display indicating, for example, “maintaining cognitivefunctions”, “maintaining a part of cognitive functions”, “amelioratingconstipation”, “ameliorating dysuria”, “ameliorating overactivebladder”, “improving renal functions”, or “maintaining cognitivefunctions and ameliorating or improving any one, two, or three ofconstipation, overactive bladder or dysuria, and renal functions”.

EXAMPLES

The present invention will be specifically described by the followingExamples, but the present invention is not limited by these Examples.

In Examples, commercial kampo medicine extracts (TSUMURA & CO.) wereused and a mixed kampo medicine of orengedokuto and ryokeijutsukantocontaining 7.5 g of orengedokuto dried extract powder and 7.5 g ofryokeijutsukanto dried extract powder was administered as a daily dose.

1. SUBJECT

The subjects were 49 patients with cognitive impairment (22 patientswith Alzheimer-type dementia, 27 patients with mild cognitiveimpairment) (male:female=5:44) followed and assessed from Jun. 18, 2002to Jul. 27, 2017, 82.0±1.1 years old in average age. Among 49 patients,9 patients were in the control group (4 patients with Alzheimer-typedementia, 5 patients with mild cognitive impairment) and 40 patientswere in the treatment group of the mixed kampo medicine of orengedokutoand ryokeijutsukanto (18 patients with Alzheimer-type dementia, 22patients with mild cognitive impairment). All the 49 subjects hadmultiple complications, but among 40 patients in the treatment group ofthe mixed kampo medicine of orengedokuto and ryokeijutsukanto, 92.5%(37/40) had complications with any of constipation, overactive bladder,and chronic kidney disease (17 patients of 18 patients withAlzheimer-type dementia, 20 patients of 22 patients with mild cognitiveimpairment), 72.5% (29/40) had complications with constipation (12patients of 18 patients with Alzheimer-type dementia, 17 patients of 22patients with mild cognitive impairment), 82.5% (33/40) hadcomplications with overactive bladder (15 patients of 18 patients withAlzheimer-type dementia, 18 patients of 22 patients with mild cognitiveimpairment), and 50% (20/40) had chronic kidney disease (9 patients of18 patients with Alzheimer-type dementia, 11 patients of 22 patientswith mild cognitive impairment). Moreover, 13 patients had complicationswith 3 diseases, 19 patients had complications with 2 diseases, 5patients had complications with 1 disease, 3 patients had nocomplication with any of the 3 diseases. Among 9 patients in the controlgroup, 88.9% (8/9) had complications with any of constipation,overactive bladder, and chronic kidney disease, 55.6% (5/9) hadcomplications with constipation, 33.3% (3/9) had complications withoveractive bladder, 55.6% (5/9) had complications with chronic kidneydisease, 1 patient had complications with the 3 diseases ofconstipation, overactive bladder, and chronic kidney disease, 3 patientshad complications with 2 diseases, 4 patients had complications with 1disease, and 1 patient had no complication with any of the 3 diseases.

2. METHOD

Alzheimer-type dementia of the subjects was clinically diagnosed bydiagnostic criteria in the ICD-10 and diagnostic imaging such as headMRI, and mild cognitive impairment was clinically diagnosed by thediagnostic criteria by Petersen et al. in 2003 (Petersen R C, et al.,Arch Neurol 62: 1160-1163, 2005) and diagnostic imaging such as headMRI. Since the correlation between Hasegawa Dementia Scale-Revised(HDS-R) and Mini-Mental-State Examination (MMSE) was 0.94 and very high(Shinji Kato, et al., Development of the revised version of Hasegawa'sDementia Scale (HDS-R), Japanese journal of geriatric psychiatry, vol.2, issue 11, 1339-1347. 1991), and the discrimination of dementia washighly reproducible regardless of the age and the duration of educationin year with a sensitivity and a specificity of 0.90 and 0.82respectively, when the cut-off value for HDS-R was set to 20/21 points,the disease course and the therapeutic effect were scored and expressedwith HDS-R taking objectivity into consideration highly.

Constipation was classified and diagnosed based on ROME III (LongstrethG F, et al., Gastroenterology 130: 1480-1491, 2006).

Overactive bladder was diagnosed by using Clinical guidelines foroveractive bladder by the Japanese Continence Society and the course wasobserved by Overactive Bladder Symptom Score (OABSS). Since manypatients use diapers and there were obstacles for diagnosis, overactivebladder was diagnosed when there is a feeling of urinary urgency and thenumber of nighttime urination was 3 times or more. When theadministration of a mixed kampo medicine of orengedokuto andryokeijutsukanto resulted in one time or less of nighttime urination, itwas determined as effective. As to the determination of therapeuticeffect on constipation, it was determined effective when the bowelmovement occurred once in 2 days or less and the bowel movement occurredsmoothly after the therapy. The chronic kidney disease was diagnosedbased on Criteria for chronic kidney disease diagnosis by the JapaneseSociety of Nephrology revised from KDIDO CKD guideline 2012 for Japaneseand the disease course was expressed by eGFR (estimated glemerularfiltration rate) with the normal value of eGFR defined as 60ml/min./1.73 m² or more. The established diagnostic criteria wereadapted for the cases for which the course had been observed sincebefore the establishment of diagnostic criteria and expressed.

The drug used was a mixed kampo medicine of orengedokuto andryokeijutsukanto and the efficacy was determined by comparing before andafter administration and with the control group. The observation periodof the 49 subjects was 810.0±126.0 days (56 days to 4,883 days) and theobservation period of the administration group of the mixed kampomedicine of orengedokuto and ryokeijutsukanto was 731.2±875.3 days. Thecontrol group was assessed for 1152±883.4 days from the start of theobservation to the end of the observation (318 days to 2905 days). Forthe statistic processing, mean±SD or mean±SE, T-test, Chi square testwere used.

3. RESULT

The age and HDS-R of the control group (n=9) at the starting time of theobservation were 83.56±5.25 years old and 20.67±6.52 respectively, andthe age and HDS-R of the administration group of the mixed kampomedicine of orengedokuto and ryokeijutsukanto (n=40) at the startingtime were 81.5±8.02 years old and 19.95±5.94 respectively. The age andHDS-R had no significant difference between the 2 groups. Moreover, theobservation periods of the both groups had no significant difference. Inthe control group (n=9), the observation period was 1152±883.4 days andHDS-R was 20.67±6.52 at the starting time of the observation and14.56±7.73 at the ending time of the observation, which wassignificantly reduced (P<0.01) (FIG. 1). In the administration group ofthe mixed kampo medicine of orengedokuto and ryokeijutsukanto (n=40),HDS-R in an observation period of 810.0±126.0 days was 19.95±5.94 at thestarting time of the administration and 24.30±5.19 at the ending time ofthe observation, which indicates significant (p<0.001) restoration ofcognitive functions (FIG. 2). The restoration of cognitive functions wasobserved in 97.5% (39/40) of the patients. There was no significantdifference in HDS-R at the starting time of the observation and therapybetween the control group and the administration group of the mixedkampo medicine of orengedokuto and ryokeijutsukanto (FIG. 3), but HDS-Rof the administration group of the mixed kampo medicine of orengedokutoand ryokeijutsukanto was significantly higher (p<0.001) in comparisonwith HDS-R of the control group at the ending time of the observation(FIG. 4). In the administration group of the mixed kampo medicine,cognitive functions were also improved in the 3 patients having nocomplication with any of constipation, overactive bladder, and chronickidney disease. In other words, cognitive functions were significantlyrestored by the administration of the mixed kampo medicine oforengedokuto and ryokeijutsukanto.

Five patients, 55.6% of the control group (n=9) had complications withconstipation and none of them was relieved during the observationperiod. 29 patients, 72.5% of the administration group of the mixedkampo medicine of orengedokuto and ryokeijutsukanto (n=40) hadconstipation and 24 patients, 82.8% of the 29 patients had relief ofconstipation by the administration of the mixed kampo medicine oforengedokuto and ryokeijutsukanto (10 patients of 12 patients withAlzheimer-type dementia, 14 patients of 17 patients with mild cognitiveimpairment), indicating a significant relief from constipation by theadministration of the mixed kampo medicine of orengedokuto andryokeijutsukanto, in comparison with the control group (p<0.01).

Three patients, 33.3% of the control group (n=9) had complications withoveractive bladder and none of them was relieved during the observationperiod. 33 patients, 82.5% of the administration group of the mixedkampo medicine of orengedokuto and ryokeijutsukanto (n=40) hadcomplications with overactive bladder and 25 patients, 79.3% of the 33patients (14 patients of 15 patients with Alzheimer-type dementia, 11patients of 18 patients with mild cognitive impairment) were relieved bythe administration of the mixed kampo medicine of orengedokuto andryokeijutsukanto, indicating significant relief from overactive bladderby the administration of the mixed kampo medicine of orengedokuto andryokeijutsukanto in comparison with the control group (p<0.05).

As to the chronic kidney disease, the eGFR in the control group (n=8)was 62.93±16.53 at the starting time of the observation and 52.52±14.00at the ending time of the observation, which indicates significant(p<0.01) decrease, the eGFR in the administration group of the mixedkampo medicine of orengedokuto and ryokeijutsukanto (n=40) was62.20±19.08 at the starting time of the administration and 62.00±17.59at the ending time of the observation, with no significant differenceand no decrease in eGFR. Moreover, no patients in the control group hadchronic kidney disease at the starting time of the observation, but50.0% (4/8) had chronic kidney disease at the ending time of theobservation. 50% (20/40) of the patients in the administration group ofthe mixed kampo medicine had chronic kidney disease at the starting timeof the administration of the mixed kampo medicine of orengedokuto andryokeijutsukanto, but there was no significant decrease in eGFR afterthe administration of the mixed kampo medicine (46.71+2.18 vs.48.51±2.02) (mean±SE). Furthermore, the eGFR in 13 patients, 65.0% of 20patients, was increased by the administration of the mixed kampomedicine of orengedokuto and ryokeijutsukanto, in comparison with thatat the starting time of the administration.

4. CONCLUSION

The mixed kampo medicine of orengedokuto and ryokeijutsukanto is a drugcharacterized by improving cognitive functions in Alzheimer-typedementia or mild dementia and relieving constipation, overactivebladder, and chronic kidney disease complicated by them at high rates,and being capable of treating even multimorbidity of any combination ofconstipation, overactive bladder, and chronic kidney disease withAlzheimer-type dementia or mild dementia.

INDUSTRIAL AVAILABILITY

By using a composition comprising a drug combination of orengedokuto andryokeijutsukanto as an active ingredient according to the presentinvention, Alzheimer-type dementia or mild cognitive impairment and atleast one disease from the group consisting of overactive bladder,constipation, and chronic kidney disease complicated by them can betreated with one drug.

What is claimed is:
 1. A kampo medicine for treating multimorbidity withone drug, comprising a drug combination of orengedokuto (Formulaantidote coptidis) and ryokeijutsukanto (Formula glycyrrhizaeatractylodis cinnamomi hoelen) as an active ingredient, wherein thekampo medicine improves a cognitive function in Alzheimer-type dementiaand relieves and treats at least one disease from overactive bladder,constipation, and chronic kidney disease complicated by Alzheimer-typedementia at a high rate with one drug.
 2. A kampo medicine for treatingmultimorbidity with one drug, comprising a drug combination oforengedokuto (Formula antidote coptidis) and ryokeijutsukanto (Formulaglycyrrhizae atractylodis cinnamomi hoelen) as an active ingredient,wherein the kampo medicine improves a cognitive function in mildcognitive impairment and relieves and treats at least one disease fromoveractive bladder, constipation, and chronic kidney disease complicatedby mild cognitive impairment at a high rate with one drug.